Calcium signaling in mouse oocyte maturation: the roles of STIM1, ORAI1 and SOCE

Abstract

Calcium handling is critical for the oocyte function, since the first steps of fertilization are dependent on the appropriate Ca(2+) mobilization to originate transient spikes of the cytosolic Ca(2+) concentration. It is well known that the Ca(2+) influx from the extracellular milieu is required to maintain this signaling in mammalian oocytes. However, the regulation of the Ca(2+) channels involved in this process is still unknown in oocytes. STIM1, a key regulator of store-operated Ca(2+) entry (SOCE), relocates in the mouse oocyte shortly after sperm stimulation, suggesting that SOCE is involved in the maintenance of cytosolic Ca(2+)-spiking in the fertilized oocyte. Here, we show that there is an up-regulation of the expression of STIM1 at the germinal vesicle breakdown stage, and this expression remains steady during following maturation stages. We found that oocytes express ORAI1, a store-operated Ca(2+) channel, and that ORAI1 expression level was stable during oocyte maturation. Immature oocytes showed no Ca(2+) entry and no increase in STIM1-ORAI1 colocalization in response to the store depletion induced by thapsigargin. On the contrary, in mature oocytes, STIM1-ORAI1 colocalization is enhanced 3-fold by depletion of Ca(2+) stores, enabling the activation of store-operated calcium channels and therefore Ca(2+) entry. Finally, the correlation between SOCE activation during the maturation of oocytes and STIM1-ORAI1 colocalization strongly suggests that ORAI1 is involved in the Ca(2+) entry pathway in the mature oocyte. SOCE up-regulation in the final stage of maturation is further evidence of a major role for SOCE in fully mature oocytes, and therefore in Ca(2+) signaling at fertilization.

Down-regulation of store-operated Ca2+ entry during mammalian meiosis is required for the egg-to-embryo transition

“…The distribution of STIM1 and Orai1 we observe is distinct from that previously reported in mouse oocytes (Gómez-Fernández et al, 2009;Gómez-Fernández et al, 2012) where STIM1 was described to localize to distinct vesicular-like ER structures before store depletion and to large ER areas after store depletion. Orai1 distribution was described as patchy membrane localized in MII eggs.…”

“…Surprisingly however in both mouse and pig oocytes previous reports detected little or no SOCE in GV oocytes (Gómez-Fernández et al, 2012;Wang et al, 2012). In contrast we detect a robust SOCE in GV oocytes in the mouse that is significantly larger than that measured in MII cells.…”

Calcium signaling and cell proliferation

“…relation was demonstrated between Ca 2+ oscillation and STIM1 expression and activity, other studies showed a link between cell proliferation/apoptosis, PLC, NF-κB, STIM1, Orai1 and Ca 2+ oscillations [43,[88][89][90][91][92].…”

“…The studies imply that primary function of a large Ca 2+ oscillatory signals might be ensure sufficient store depletion by robust activation of CRAC channels through STIM1, activating downstream signal transduction [43,[88][89][90][91][92]. Additionally, two different transcription factors, c-fos and NFAT were shown to promote local Ca 2+ elevations near open CRAC channels and activate gene expression [42,93].…”

CaV3.2 T-type channels mediate Ca2+ entry during oocyte maturation and following fertilization

“…Based on these observations, SOCE, which relies upon detection of low ER Ca 2+ by STIM1 and STIM2 proteins, which promote Ca 2+ influx through ORAI channels (reviewed in Bird et al, 2008;Putney, 2007), might be considered a prime candidate for mediating the Ca 2+ influx needed to sustain Ca 2+ oscillations in mammalian eggs. Although SOCE components are present in mouse oocytes and eggs (Cheon et al, 2013;, and previous reports have suggested that SOCE might be active during mammalian oocyte maturation and fertilization (Cheon et al, 2013;Gomez-Fernandez et al, 2012Lee et al, 2012;Wang et al, 2012Wang et al, , 2015, evidence against a requisite role for SOCE is also mounting. We have previously shown that chemical inhibition of SOCE following fertilization does not impair Ca 2+ oscillations or egg activation events .…”